Drug induced liver injury (DILI) is a major cause of acute liver failure (ALF) and one of the leading indications for liver transplantation in Western societies. Given the wide use of both prescribed and over the counter drugs, DILI has become a major health issue with a pressing need to find novel and effective therapies. Although significant progress has been made in understanding the molecular mechanisms underlying DILI, our incomplete knowledge of its pathogenesis and inability to predict DILI is largely due to both discordance between human and animal DILI in preclinical drug development and a lack of models that faithfully recapitulate complex pathophysiological features of human DILI. This is exemplified by the hepatotoxicity of acetaminophen (APAP) overdose, a major cause ALF due to its extensive worldwide use as an analgesic. Despite intensive efforts utilizing current animal and in vitro models, the mechanisms involved in the hepatotoxicity of APAP are still not fully understood. This expert Consensus Statement, which is endorsed by the European Drug-Induced Liver Injury Network, has been led by Jose C Fernandez-Checa with the collaboration of Carmen Garcia Ruiz of the group “Mitochondrial Regulation of Cell Death” of the IIBB and has been published in the Journal of Hepatology. The aim of the review was to facilitate and outline clinically impactful knowledge discovery by detailing the requirements for more realistic human-based systems to assess hepatotoxicity to guide future drug safety testing. We present novel insights and major players in APAP pathophysiology and describe emerging in vitro and in vivo pre-clinical models, including humanized mouse models, as well as advanced imaging and in silico technologies, which may improve prediction of clinical outcomes of DILI including APAP hepatotoxicity. The elaboration of the consensus has been posible thanks to the participation of experts from around Europe.
Article de referència
DOI: 10.1016/j.jhep.2021.06.021
